Arsenic is ranked number one on the most recent priority list of Superfund site hazardous substances by the Agency for Toxic Substances and Disease Registry (ATSDR). We propose to continue our international arsenic biomarker epidemiology program with a new focus on the malignant and non-malignant pulmonary health effects of ingesting inorganic arsenic in drinking water. This shift in focus is related to the fact that risk estimates based on findings from three separate countries including studies performed by us in Argentina and Chile, show that lung cancer contributes more to increased mortality due to arsenic ingestion than all other arsenic-caused cancers combined. Thus, improving population cancer risk estimation is critically dependent on a better understanding of arsenic-induced lung cancer. In addition to lung cancer, evidence from our studies in West Bengal and Chile suggest that ingested arsenic way also cause chronic non-malignant pulmonary disease, which exposures during childhood being particularly important. We therefore propose several studies to investigate the malignant and non-malignant pulmonary effects originating from the ingestion of inorganic arsenic in drinking water. A lung cancer case-control study in Argentina will use individual exposure data to focus on dose-response issues and the potential synergy of arsenic with cigarette smoking. Individual susceptibility will be assessed by urinary arsenic methylation patterns, plus glutathione transferase (GST) and methylenetetrahydrofolate reductase (MTHFR) genotypes in buccal cell DNA. Long tumor DNA from both this study and a lung cancer study in chile will be assessed for genetic alterations including p53 mutations, DNA methylation, and changes detectable by comparative genomic hybridization. In chile, we will also investigate arsenic-induced chronic respiratory disease mortality in young adults in relation to childhood arsenic exposures. Chronic respiratory disease, arsenic-caused skin lesions, and nutritional susceptibility will be investigated in a study in West Bengal, India. Arsenic effects in children will be part of this study, as well as studies of children with skin lesions in Bangladesh and Chile. In summary, we propose to investigate both the malignant and non-malignant pulmonary effects of inorganic arsenic ingestion, including the health effects resulting from childhood exposure. The overall goal of this research is to provide information that will allow the population risks from arsenic in drinking water to be more accurately assessed.